Kwon, Yu jin Kim, Jiyoon Cho, Suyeon Kang yoon jin Lee, Jongsoo Kwon, Jaeyoung Rhee, Hyungjin Bauer, Sebastian Kim, Hyung-Sik Lee, Esak Kim, Han Sang Jung, Jae Hung Kim, Hoguen Kim, Won Kyu 2024-01-12T06:33:42Z 2024-01-12T06:33:42Z 2023-09-19 2023-10 1350-9047 https://pubs.kist.re.kr/handle/201004/79810 Gastrointestinal stromal tumors (GISTs) frequently show KIT mutations, accompanied by overexpression and aberrant localization of mutant KIT (MT-KIT). As previously established by multiple studies, including ours, we confirmed that MT-KIT initiates downstream signaling in the Golgi complex. Basic leucine zipper nuclear factor 1 (BLZF1) was identified as a novel MT-KIT-binding partner that tethers MT-KIT to the Golgi complex. Sustained activation of activated transcription factor 6 (ATF6), which belongs to the unfolded protein response (UPR) family, alleviates endoplasmic reticulum (ER) stress by upregulating chaperone expression, including heat shock protein 90 (HSP90), which assists in MT-KIT folding. BLZF1 knockdown and ATF6 inhibition suppressed both imatinib-sensitive and -resistant GIST in vitro. ATF6 inhibitors further showed potent antitumor effects in GIST xenografts, and the effect was enhanced with ER stress-inducing drugs. ATF6 activation was frequently observed in 67% of patients with GIST (n？=？42), and was significantly associated with poorer relapse-free survival (P？=？0.033). Overall, GIST bypasses ER quality control (QC) and ER stress-mediated cell death via UPR activation and uses the QC-free Golgi to initiate signaling. English Nature Publishing Group Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT Article 10.1038/s41418-023-01220-2 1 Cell Death & Differentiation, v.30, no.10, pp.2309 - 2321 Cell Death & Differentiation 30 10 2309 2321 N scie scopus 001067496200001 Biochemistry & Molecular Biology Cell Biology Biochemistry & Molecular Biology Cell Biology Article STRESS-RESPONSE PROTEIN ACTIVATION EXPRESSION MUTATIONS MEMBRANE RECEPTOR THERAPY OCCURS CELLS